Myelo-immunosuppressive therapy followed by blood and marrow transplantation (BMT) offers great promise for cure of most hematologic malignancies, a number of solid cancers, and a variety of fatal nonmalignant disorders. Nevertheless at present, only a minority of patients with diseases potentially curable by BMT are indeed cured, since many are not eligible for BMT and a significant number who are transplanted die of toxicity or disease recurrence. The ability to identify, isolate, and manipulate lympho-hematopoietic stem-progenitor cells (HSCs) will improve both the availability and outcome of BMT. The overall goals of this competitive renewal Program Project proposal are to better understand the pathophysiology of normal HSCs and abnormal HSCs in human diseases. Based on this understanding, we propose to develop specific laboratory methods to make HSCs better transplantation tools, for severe aplastic anemia (SAA), PNH, MDS and leukemia, and for BMT in general. Specifically, we propose in this Program Project to: 1. further improve our novel and highly effective immunoablative but non-myeloablative treatment for SAA (Projects 1, 2), 2. develop increased understanding of the pathogenesis of SAA and PNH (Projects 1, 2, 3, 4), 3. investigate the role and regulation of FLT3 in normal and diseased HSCs (Projects 3, 2, 1), and 4. molecularly describe apoptotic pathway status of T/NK cells mediating graft vs. host disease(GVHD) and SAA, as well as HSCs in SAA and PNH; determine if cells transduced to constitutively express the Fas Ligand (FasL) gene functionally protect allogeneic host cells from immune attack in GVHD and autologous HSCs from immune attack in SAA/PNH (Projects 4, 2, 1).